The first small molecule drug discovered with the aid of neural stem cells has significantly affected major depressive disorder (MDD) in a small group of patients, Harvard neurologists report this week.
The drug, called NSI-189, is a benzylpiperizine-aminiopyridine, was found in preclinical work to prompt new neuron formation, both in mouse models and in cultures of human hippocampus-derived cells. (The preclinical work was not published, but it was funded by DARPA and the National Institutes of Health.)  Harvard’s Marlene Freeman, medical director of the Massachusetts General Hospital’s Clinical Trials Network and Institute (MGH CTNI), will report at the American Society of Clinical Psychopharmacology meeting on Wednesday that depressed patients taking two different doses of the drug have now experienced a “clinically meaningful” relief of depressive and cognitive symptoms across all measures in comparison to placebo. This relief continued throughout the follow-up period. 
Patients’ depressive and cognitive symptoms improved via measurements including the Montgomery-Asberg Depression Rating Scale (MADRS); the Clinician Global Impression -- Improvement (CGI-I); the Symptoms of Depression Questionnaire (SDQ) and the Cognitive and Physical Functioning Questionnaire (CPFQ). 
“This is really the coming out party for neurogenesis,” Neuralstem CEO Richard Garr told Drug Discovery & Development via email. Neuralstem created the drug, and tested it on is fetal neural stem cells. “This really is a first-in-class neurogenic drug. The data on depression are very good, and the cognitive improvement is very exciting and never seen before. But the key for us is that both effects persisted as far as we measured, which was two months after we had stopped giving the patients the medicine. There is no accumulation of the drug in the patients. So this is a very solid sign pointing to confirming our thesis that what we see in animals—structurally rebuilding the hippocampus—is also happening in humans.”
Maurizio Fava, executive vice chair, Harvard Department of Psychiatry, and executive director of the MGH CTNI, will present the complete data from this Phase 1b trial on Tuesday. His Harvard team will present biomarker data from the trial at the International College of Neuropsychopharmacology World Congress in Vancouver.
The drug was identified by screening scores of compounds in dishes of human fetal neural stem cells generated by Neuralstem. The best candidates – to cause neural stem cells to grow into neurons – were tried on animal models. Fava will note at the conference that a neurogenesis - based platform accurately identifies effective new treatments for major depressive disorder.
The clinical trial was an early phase, double-blind, randomized, placebo-controlled, multiple-dose study with three ascending cohorts. The first cohort received 40 mg QD (every day); the second cohort 40 mg BID (twice daily); and the third cohort 40 mg TID (thrice daily). Twenty four patients with major depressive disorder were enrolled. Their diagnoses were ascertained via an independent, remote SAFER interview from the MGH CTNI raters. Each cohort included at least three female subjects. 
Each patient underwent a screening for eligibility, and eligible patients were admitted into the unit on Day 5 to complete their wash-out and be reconfirmed for eligibility and for baseline assessments. 
Eligible patients received daily dosing of NSI-189 Phosphate or placebo for 28 days starting on Day 1 and were followed for safety, PK, and PD until discharge. At the conclusion of in-house dosing (Day 28), patients remained in the unit for up to three additional days, at the psychiatrist’s discretion.
On Day 35, Day 42, Day 49, and Day 70, outpatient follow-up visits took place. Patients returned to the unit for extensive follow-up on Day 56 and Day 84 (end-of-study). 
Despite the minimal improvement observed among the placebo-treated patients, at day 28, the efficacy measurements showed a clinically meaningful reduction in depressive and cognitive symptoms across all measures for the two lower doses (40 mg/day and 80 mg/day) but not for the highest dose (120 mg/day). These improvements appeared to persist over time during the follow-up for MADRS, SDQ, and CPFQ. In terms of safety, no serious adverse Events occurred and the drug was well tolerated. 
The main limitations: the small sample size of each cohort and the fact that efficacy analyses were not the primary aim.
These preliminary findings support Fava’s past findings, using other drugs, that new neurogenesis can appear to promote relief of MDD symptoms. The possible inverted U dose-response curve seen in the current study has been seen in studies of compounds enhancing synaptic plasticity. Further studies are necessary.
Garr told Drug that other anti-depressives appear to have some neurogenic ability in times of stress, but that NSI-189 is far more neurogenic in both healthy animals and animals in stress. This study has not yet been published in a peer-reviewed journal.